Arginine

Arginine is classified as a semiessential or conditionally essential amino acid, depending on the developmental stage and health status of the individual.[13] Preterm infants are unable to synthesize arginine internally, making the amino acid nutritionally essential for them.[14] Most healthy people do not need to supplement with arginine because it is a component of all protein-containing foods[15] and can be synthesized in the body from glutamine via citrulline.[16][17] Additional dietary arginine is necessary for otherwise healthy individuals temporarily under physiological stress, for example during recovery from burns, injury or sepsis,[17] or if either of the major sites of arginine biosynthesis, the small intestine and kidneys, have reduced function, because the small bowel does the first step of the synthesizing process and the kidneys do the second.[3]

arginine

Arginine is an essential amino acid for birds, as they do not have a urea cycle.[18] For some carnivores, for example cats, dogs[19] and ferrets, arginine is essential,[3] because after a meal, their highly efficient protein catabolism produces large quantities of ammonia which need to be processed through the urea cycle, and if not enough arginine is present, the resulting ammonia toxicity can be lethal.[20] This is not a problem in practice, because meat contains sufficient arginine to avoid this situation.[20]

Arginine is made by the body as follows. The epithelial cells of the small intestine produce citrulline, primarily from glutamine and glutamate, which is secreted into the bloodstream which carries it to the proximal tubule cells of the kidney, which extract the citrulline and convert it to arginine, which is returned to the blood. This means that impaired small bowel or renal function can reduce arginine synthesis and thus create a dietary requirement for arginine. For such a person, arginine would become "essential".

Synthesis of arginine from citrulline also occurs at a low level in many other cells, and cellular capacity for arginine synthesis can be markedly increased under circumstances that increase the production of inducible nitric oxide synthase (NOS). This allows citrulline, a byproduct of the NOS-catalyzed production of nitric oxide, to be recycled to arginine in a pathway known as the citrulline to nitric oxide (citrulline-NO) or arginine-citrulline pathway. This is demonstrated by the fact that, in many cell types, nitric oxide synthesis can be supported to some extent by citrulline, and not just by arginine. This recycling is not quantitative, however, because citrulline accumulates in nitric oxide producing cells along with nitrate and nitrite, the stable end-products of nitric oxide breakdown.[23]

Arginine's side chain is amphipathic, because at physiological pH it contains a positively charged guanidinium group, which is highly polar, at the end of a hydrophobic aliphatic hydrocarbon chain. Because globular proteins have hydrophobic interiors and hydrophilic surfaces,[32] arginine is typically found on the outside of the protein, where the hydrophilic head group can interact with the polar environment, for example taking part in hydrogen bonding and salt bridges.[33] For this reason, it is frequently found at the interface between two proteins.[34] The aliphatic part of the side chain sometimes remains below the surface of the protein.[33]

Arginine residues in proteins can be deiminated by PAD enzymes to form citrulline, in a post-translational modification process called citrullination.This is important in fetal development, is part of the normal immune process, as well as the control of gene expression, but is also significant in autoimmune diseases.[35] Another post-translational modification of arginine involves methylation by protein methyltransferases.[36]

Arginine is also a precursor for urea, ornithine, and agmatine; is necessary for the synthesis of creatine; and can also be used for the synthesis of polyamines (mainly through ornithine and to a lesser degree through agmatine, citrulline, and glutamate.) The presence of asymmetric dimethylarginine (ADMA), a close relative, inhibits the nitric oxide reaction; therefore, ADMA is considered a marker for vascular disease, just as L-arginine is considered a sign of a healthy endothelium.

The amino acid side-chain of arginine consists of a 3-carbon aliphatic straight chain, the distal end of which is capped by a guanidinium group, which has a pKa of 13.8,[37] and is therefore always protonated and positively charged at physiological pH. Because of the conjugation between the double bond and the nitrogen lone pairs, the positive charge is delocalized, enabling the formation of multiple hydrogen bonds.

Intravenously administered arginine is used in growth hormone stimulation tests[38] because it stimulates the secretion of growth hormone.[39] A review of clinical trials concluded that oral arginine increases growth hormone, but decreases growth hormone secretion, which is normally associated with exercising.[40] However, a more recent trial reported that although oral arginine increased plasma levels of L-arginine it did not cause an increase in growth hormone.[41]

Research from 1964 into amino acid requirements of herpes simplex virus in human cells indicated that "...the lack of arginine or histidine, and possibly the presence of lysine, would interfere markedly with virus synthesis", but concludes that "no ready explanation is available for any of these observations".[42]

Supplementation with l-arginine reduces diastolic blood pressure and lengthens pregnancy for women with gestational hypertension, including women with high blood pressure as part of pre-eclampsia. It did not lower systolic blood pressure or improve weight at birth.[48]

Both liquid chromatography and liquid chromatography/mass spectrometric assays have found that brain tissue of deceased people with schizophrenia shows altered arginine metabolism. Assays also confirmed significantly reduced levels of γ-aminobutyric acid (GABA), but increased agmatine concentration and glutamate/GABA ratio in the schizophrenia cases. Regression analysis indicated positive correlations between arginase activity and the age of disease onset and between L-ornithine level and the duration of illness. Moreover, cluster analyses revealed that L-arginine and its main metabolites L-citrulline, L-ornithine and agmatine formed distinct groups, which were altered in the schizophrenia group. Despite this, the biological basis of schizophrenia is still poorly understood, a number of factors, such as dopamine hyperfunction, glutamatergic hypofunction, GABAergic deficits, cholinergic system dysfunction, stress vulnerability and neurodevelopmental disruption, have been linked to the aetiology and/or pathophysiology of the disease.[49]

There are plenty of powerful new drugs to help prevent and treat chronic health problems. But we also know that certain nutrients may help, as well. Take arginine, for example. Arginine has gotten lots of attention lately for its potential heart benefits. That's important because, today, more than 85 million Americans have some form of cardiovascular disease.

Deficiencies of arginine are rare. It's abundant in many different types of foods, and your body can also make it. Arginine-rich foods include red meat, fish, poultry, wheat germ, grains, nuts and seeds, and dairy products. But what does arginine do for the heart, and are there potential side effects?

Some evidence shows that arginine may help improve blood flow in the arteries of the heart. That may improve symptoms of clogged arteries, chest pain or angina, and coronary artery disease. However, there currently is no data on how the long-term use of arginine affects cholesterol or heart health.

There are other potential health benefits with arginine, such as possible reduction of blood pressure in some people and improved walking distance in patients with intermittent leg cramping and weakness known as intermittent claudication. However, the scientific studies are not conclusive enough for experts to make any firm recommendations.

In clinical trials, arginine has been used safely with minor side effects for up to three months. Possible side effects include abdominal pain and bloating, diarrhea, and gout. It may also cause a worsening of breathing in people with asthma.

Daily supplementation with arginine can reduce blood pressure in people with healthy blood pressure and people with hypertension (high blood pressure).[179] Evidence also supports the use of arginine to help improve birth outcomes in pregnant women with conditions like hypertension and preeclampsia or a history of poor pregnancy outcomes. This includes reducing the risk of infants small for gestational age[180] and intrauterine growth restriction of the baby.[181] Arginine can also improve maternal outcomes by reducing the risk of preeclampsia in the pregnant mother.[182][183] Additionally, arginine can reduce blood triglycerides,[184][185] particularly in people older than 50 or in people with metabolic syndrome or type 2 diabetes.[184]

In men with erectile dysfunction, daily supplementation with arginine can alleviate symptoms.[186] Furthermore, the combination of arginine with phosphodiesterase type 5 inhibitors (PDE5Is), like Viagra, improves sexual function in men with erectile dysfunction more than treatment with PDE5Is alone.[187]

Evidence also shows that daily supplementation with arginine might increase VO2max, but the magnitude of improvement is negligible and unlikely to be clinically meaningful.[188] Furthermore, most studies find no beneficial effect of arginine on exercise performance.[189] It is only when highly-varied types of exercise (aerobic, anaerobic, resistance, etc.) and performance outcomes (time-to-exhaustion, time-trials, sprint time, 1-rep-max, reps-to-failure, etc.) are inappropriately pooled that meta-analyses find a performance benefit from arginine.[189]

Animal studies show that neither oral nor intravenous delivery of arginine causes toxicity, even at high doses.[190][191] However, supplementation with arginine has been reported to cause adverse gastrointestinal effects in humans, including nausea, vomiting, and diarrhea.[192] For this reason, upper limit guidelines of approximately 20 to 30 grams per day have been proposed for supplemental arginine intake,[193][194] but more long-term safety data in humans are needed to accurately define a tolerable upper intake level. 041b061a72